Neurotrophic factors play important roles not only in the development of the nervous system, but also in maintenance of its function and plasticity. GDNF (Glial cell line-Derived Neurotrophic Factor) is essential for growth, development and plasticity of dopamine and motor neurons as well as other brain cell populations (Airaksinen, M. S. et al. 2002). In the brain, GDNF is released by both neurons and glia cells. Although the signaling mechanisms underlying the expression and release of GDNF are not fully mapped, the released GDNF exerts its function on the brain cells and neurocircuitry through a receptor complex, comprised of GFRα1 (GDNF Family Receptor α1) and receptor tyrosine kinase RET (Trupp, M. et al. 1997). On the basis of the trophic and repair effects GDNF has on neural cells, it was considered as a potential therapeutic agent for several neurological disorders. However, GDNF is a protein and thus not readily administered to the brain. Consequently, small molecule inducers of GDNF release are of interest as potential therapeutics, most notably in the context of Parkinson's disease and neuropathic pain. In the latter case, GDNF's effectiveness has been ascribed to the ability of GDNF signaling to reset the function of several sodium channel subunits (modified in response to injury) (Boucher, T. J. et al. 2000).
Recently, it has been shown that GDNF (Glial cell line-Derived Neurotrophic Factor) acts as a negative regulator of alcohol addiction in rodent behavioral models (Carnicella, S. et al. 2008) It has also been demonstrated that the small molecule agents, ibogaine and noribogaine, reduce self-administration and reinstatement of alcohol intake in rats and mice, and that this effect is dependent on the induction of GDNF in the VTA (Ventral Tegmental Area of midbrain) (He, D-Y. et al. 2005; Carnicella, S. et al. 2010). However, ibogaine is active at multiple CNS receptors, resulting in complex pharmacology and serious side effects. Therefore, compounds that act as selective GDNF inducers are desirable. In addition to alcohol, GDNF also counteracts behavioral and biochemical adaptations in mice chronically treated with cocaine and morphine (Messer, C. J. et al. 2000; Bolanos, C. A. et al. 2004). Therefore, the GDNF inducing compounds may also be effective against other substance use disorders (SUDs).
GDNF also plays an important role in cognition and the changes in GDNF levels have been associated with mood disorders and the treatment of depression (Takebayashi, M. et al. 2006). Consequently, GDNF inducers should be considered as potential therapeutics for depressive disorders.
Described herein is a new class of GDNF (Glial cell line-Derived Neurotrophic Factor) inducers based on the isoquinuclidine core (FIG. 1).